Inhibition of the epigenetic suppressor EZH2 primes osteogenic differentiation mediated by BMP2.
Bone-stimulatory therapeutics include bone morphogenetic proteins (e.g. BMP2), parathyroid hormone, and antibody-based suppression of WNT antagonists. Inhibition of the epigenetic enzyme enhancer of zeste homolog 2 (EZH2) is both bone anabolic and osteoprotective. EZH2 inhibition stimulates key components of bone-stimulatory signaling pathways, including the BMP2 signaling cascade. Because of high costs and adverse effects associated with BMP2 use, here we investigated whether BMP2 dosing can be reduced by co-treatment with EZH2 inhibitors. Co-administration of BMP2 with the EZH2 inhibitor GSK126 enhanced differentiation of murine (MC3T3) osteoblasts, reflected by increased alkaline phosphatase activity, Alizarin Red staining, and expression of bone-related marker genes (e.g. Bglap and Phospho1). Strikingly, co-treatment with BMP2 (10 ng/ml) and GSK126 (5 μm) was synergistic and was as effective as 50 ng/ml BMP2 at inducing MC3T3 osteoblastogenesis. Similarly, the BMP2-GSK126 co-treatment stimulated osteogenic differentiation of human bone marrow-derived mesenchymal stem/stromal cells, reflected by induction of key osteogenic markers (e.g. Osterix/SP7 and IBSP). A combination of BMP2 (300 ng local) and GSK126 (5 μg local and 5 days of 50 mg/kg systemic) yielded more consistent bone healing than single treatments with either compound in a mouse calvarial critical-sized defect model according to results from μCT, histomorphometry, and surgical grading of qualitative X-rays. We conclude that EZH2 inhibition facilitates BMP2-mediated induction of osteogenic differentiation of progenitor cells and maturation of committed osteoblasts. We propose that epigenetic priming, coupled with bone anabolic agents, enhances osteogenesis and could be leveraged in therapeutic strategies to improve bone mass.


Expectations and satisfaction with antenatal care among pregnant women with a focus on vulnerable groups: a descriptive study in Ghent.
Previous studies demonstrate that people's satisfaction with healthcare influences their further use of that healthcare system. Satisfied patients are more likely to take part in the decision making process and to complete treatment. One of the important determinants of satisfaction is the fulfillment of expectations. This study aims to analyse both expectations and satisfaction with antenatal care among pregnant women, with a particular focus on vulnerable groups. A quantitative descriptive study was conducted in 155 women seeking antenatal care at the University Hospital of Ghent (Belgium), of whom 139 completed the questionnaire. The statistical program SPSS-21 was used for data analysis. Women had high expectations relating to continuity of care and women-centered care, while expectations regarding availability of other services and complete care were low. We observed significantly lower expectations among women without higher education, with low income, younger than 26 years and women who reported intimate partner violence. General satisfaction with antenatal care was high. Women were satisfied with their relationship with the healthcare worker, however ; they evaluated the information received during the consultation and the organizational aspects of antenatal care as less satisfactory. In order to improve satisfaction with antenatal care, organizational aspects of antenatal care (e.g. reducing waiting times and increasing accessibility) need to be improved. In addition, women would appreciate a better provision of information during consultation. More research is needed for an in-depth understanding of the determinants of satisfaction and the relationship with low socio economic status (SES).


Sequelae of sexual trauma in women treated for non-trauma-related psychiatric disorders in a psychiatric hospital in Switzerland.
We sought to explore the impact of sexual trauma on symptom severity, sense of coherence, and control orientation in female psychiatric inpatients diagnosed with and admitted for non-trauma-related mental disorders. A sample of 31 female inpatients with a reported history of sexual trauma (two thirds abused in childhood, one third raped in adulthood) were compared with 31 female inpatients with similar sociodemographic backgrounds, matched for age and psychiatric diagnosis. Compared with the sexually nontraumatized patients, the patients with a reported history of sexual trauma were neither more symptomatic nor did they have a more severe course of illness. No significant differences were found between the two groups with regard to sense of coherence and control orientation. Patients who had been raped in adulthood rated lower than all other patients in the Meaningfulness subscale of the Sense of Coherence Scale, indicating that their belief that there is good reason to care about what happens has been affected. Based on the dimensions assessed, female psychiatric inpatients with a reported history of sexual trauma were not found to be significantly different from female inpatients without such a history. The burden of a mental disorder ensuing from the severity of illness symptoms and illness course is probably so high that the potential impact of a sexual trauma cannot manifest.


Lactose malabsorption and intolerance: a review.
Food lactose and lactose intolerance are today hot topics in the field of food and nutrition. About 70% of the adult world population is lactose-intolerant, due to low levels of intestinal lactase, also called lactase-phlorizin hydrolase (LPH), a β-d-galactosidase found in the apical surface of the intestinal microvilli. This may be due to the loss of intestinal lactase in adulthood, a condition transmitted by an autosomal recessive gene, which differs in humans according to race. According to the cultural-historical hypothesis, the mutation that allows the metabolization of lactose appeared about 10 000 years ago in the inhabitants of Northern Europe where mammalian milk continued in the diet after weaning, and lactase-persistent populations were genetically selected in some areas. Many intolerant individuals can tolerate low levels of lactose in their daily diet. Probiotics have also been proposed as an alternative that could avoid some symptoms of lactose intolerance. Many products are marketed nowadays as alternatives to dairy products for lactose-intolerant individuals. However, the rules for low-lactose foods are currently not harmonised in the European Union. As scientific knowledge on lactose intolerance has notably advanced in recent decades, the aim of this work was to review the current state of the knowledge on lactose and lactose intolerance, its diagnosis and clinical management, and the various food products that are offered specifically for non-tolerant individuals.


Processing of voided urine for prostate cancer RNA biomarker analysis.
Voided urine samples have been shown to contain cells released from prostate tumors. Could good quality RNA from cells in urine be obtained from every donor for multimarker analysis? In addition, could urine donation be as simple as possible, a practical consideration for a lab test, without involving a prostate massage (as indicated for PCA3 testing), which precludes frequent collection; needing it done at a specific time of day (e.g., first or second urine); and requiring prompt processing of samples in clinics with limited molecular biology capability? Collected urine samples were pelleted, and the RNA isolated was processed for cDNA synthesis and in vitro transcription to generate amplified sense aRNA. The resultant aRNA was rigorously analyzed for possible introduced changes. DMSO was used as a cell preservative for frozen storage of urine samples. Good quality aRNA was obtained for over 100 samples collected at two different institutions. The process of RNA amplification removed co-isolated DNA in some samples, which did not affect RNA amplification. Amplification did not amplify genes that were absent and produce other expression alterations. The sense aRNA could be used to generate urinary transcriptomes specific to individual patients. No chaotropic agents for RNA preservation were added to the urine samples so that the supernatant could be used for analysis of secreted protein biomarkers. The time of donation was not important since patients were seen during the entire day. DMSO was an effective cell preservative for freezing urine. Urinary RNA can be readily isolated and amplified for prostate cancer biomarker analysis. Individual patients had unique set of transcripts derived from their tumor.


The 'healthy immigrant' effect: initial evidence for Ireland.
The period from 1996 to 2008 was one of rapid economic and social change in Ireland, with one of the most significant changes being the transition from a situation of net emigration to one of substantial net immigration. Although research on the impact of immigration on Irish society, as well as the labour market characteristics and experiences of immigrants in Ireland has increased in recent years, comparatively little is known about the health status of immigrants to Ireland. An extensive international literature has documented a 'healthy immigrant' effect for large immigrant-receiving countries such as the United States, Canada and Australia, whereby the health status of immigrants is better than comparable native-born individuals. There is also evidence to suggest that immigrants' health status deteriorates with time spent in the host country. However, the Irish immigration experience differs considerably from that of countries that have been the focus of research on the 'healthy immigrant' effect. Using microdata from a nationally representative survey of the population in 2007, this paper finds only limited evidence in favour of a 'healthy immigrant' effect for Ireland, although the distinctive features of the Irish immigrant population, and the nature of the data available, may partly explain the results.


Large-scale physical activity data reveal worldwide activity inequality.
To be able to curb the global pandemic of physical inactivity and the associated 5.3 million deaths per year, we need to understand the basic principles that govern physical activity. However, there is a lack of large-scale measurements of physical activity patterns across free-living populations worldwide. Here we leverage the wide usage of smartphones with built-in accelerometry to measure physical activity at the global scale. We study a dataset consisting of 68 million days of physical activity for 717,527 people, giving us a window into activity in 111 countries across the globe. We find inequality in how activity is distributed within countries and that this inequality is a better predictor of obesity prevalence in the population than average activity volume. Reduced activity in females contributes to a large portion of the observed activity inequality. Aspects of the built environment, such as the walkability of a city, are associated with a smaller gender gap in activity and lower activity inequality. In more walkable cities, activity is greater throughout the day and throughout the week, across age, gender, and body mass index (BMI) groups, with the greatest increases in activity found for females. Our findings have implications for global public health policy and urban planning and highlight the role of activity inequality and the built environment in improving physical activity and health.


Protective factors at school: reciprocal effects among adolescents' perceptions of the school environment, engagement in learning, and hope.
Although some research suggests that schools can be a source of protective factors for students, the processes by which school environments impact students' behavior, performance and adjustment over time are not clear. Guided by both self-determination theory and hope theory, this article evaluated reciprocal effects among adolescent perceptions of the school environment, engagement in learning, hope, and academic achievement. Using a sample of 423 students (M age 15.72 years; 46.7% female; 77.6% white; 30.9% eligible for FRPL) from five small secondary schools in the upper Midwest, students' perceptions of the school environment were linked to engagement in learning, which, in turn, was linked to change in academic achievement and hope over the span of 1 year. Evidence was found for reciprocal links between earlier levels of engagement and hope and later perceptions of the environment. These results suggest that the school environment represents a potential leverage point for educational reform, and interventions that target students' perceptions of autonomy, teacher/peer support, and goal orientation may be able to promote engagement, hope, and academic achievement. In addition, such changes may create a positive feedback loop in which change in academic performance and adjustment accelerate over time.


[Brain substrates of episodic memory disorders in Alzheimer's disease].
Resting state PET measurement is useful to unravel brain regions whose dysfunction is responsible for impairment of episodic memory in Alzheimer's disease. First, the consistent hypometabolism of posterior cingulate cortex, temporo-parietal cortex and frontal cortex contrasts with the frequent lack of hippocampal hypometabolism, although it is first to be concerned by neurofibrillary tangles. Several hypotheses are proposed to explain this paradoxical result. Second, the correlative approach (correlations between memory performances and metabolic values on a voxel basis) shows that dysfunction of the hippocampal region is responsible for the earliest deficits of episodic memory, and then suggests the recruitment of neocortical temporal areas normally involved in semantic memory, perhaps as a form of a compensatory mechanism. When applied to the study of Mild Cognitive Impairment, this approach is also very fruitful.


Neuroimaging for Migraine: The American Headache Society Systematic Review and Evidence-Based Guideline.
To provide updated evidence-based recommendations about when to obtain neuroimaging in patients with migraine. Articles were included in the systematic review if they studied adults 18 and over who were seeking outpatient treatment for any type of migraine and who underwent neuroimaging (MRI or CT). Medline, Web of Science, and Cochrane Clinical Trials were searched from 1973 to August 31, 2018. Reviewers identified studies, extracted data, and assessed the quality of the evidence in duplicate. We assessed study quality using the Newcastle-Ottawa Scale. The initial search yielded 2269 publications. Twenty three articles met inclusion criteria and were included in the final review. The majority of studies were retrospective cohort or cross-sectional studies. There were 4 prospective observational studies. Ten studies evaluated the utility of CT only, 9 MRI only, and 4 evaluated both. Common abnormalities included chronic ischemia or atrophy with CT and MRI scanning, and non-specific white matter lesions with MRI. Clinically meaningful abnormalities requiring intervention were relatively rare. Clinically significant neuroimaging abnormalities in patients with headaches consistent with migraine without atypical features or red flags appeared no more common than in the general population. There is no necessity to do neuroimaging in patients with headaches consistent with migraine who have a normal neurologic examination, and there are no atypical features or red flags present. Grade A Neuroimaging may be considered for presumed migraine for the following reasons: unusual, prolonged, or persistent aura; increasing frequency, severity, or change in clinical features, first or worst migraine, migraine with brainstem aura, migraine with confusion, migraine with motor manifestations (hemiplegic migraine), late-life migraine accompaniments, aura without headache, side-locked headache, and posttraumatic headache. Most of these are consensus based with little or no literature support. Grade C.


Peptides for nucleic acid delivery.
Nucleic acids and their synthetic oligonucleotide (ON) analogs are a group of gene therapeutic compounds which hold enormous clinical potential. Despite their undoubted potential, clinical translation of these molecules, however, has been largely held back by their limited bioavailability in the target tissues/cells. To overcome this, many different drug delivery systems have been devised. Among others, short delivery peptides, called cell-penetrating peptides (CPPs), have been demonstrated to allow for efficient delivery of nucleic acids and their ON analogs, in both cell culture and animal models. In this review, we provide brief overview of the latest advances in nucleic acid delivery with CPPs, covering the two main vectorization strategies, covalent conjugation and nanoparticle formation-based approach. In conclusion, CPP-based drug delivery systems have the capacity to overcome the hurdle of delivery and thus have the potential to facilitate the clinical translation of nucleic acid-based therapeutics.


Explaining #theShoe based on the optimal color hypothesis: The role of chromaticity vs. luminance distribution in an ambiguous image.
The image of #theShoe is a derivative image of #theDress which induces vastly different color experiences across individuals. The majority of people perceive that the shoe has grey leather with turquoise laces, but others report pink leather with white laces. We hypothesized #theShoe presents a problem of color constancy, where different people estimate different illuminants falling onto the shoe. The present study specifically aimed to understand what cues in the shoe image caused the ambiguity based on the optimal color hypothesis: our visual system knows the gamut of surface colors under various illuminants and applies the knowledge for illuminant estimation. The analysis showed that estimated illuminant chromaticity largely changes according to the assumed intensity of the illuminant. When the illuminant intensity was assumed to be low, a high color temperature was estimated. In contrast, assuming high illuminant intensity led to the estimation of low color temperature. A simulation based on a von Kries correction showed that the subtraction of estimated illuminants from the original image shifts the appearance of the shoe towards the reported states (i.e. gray-turquoise or pink-white). These results suggest that the optimal color hypothesis provides a theoretical interpretation to #theShoe phenomenon. Moreover, this luminance-dependent color-shift was observed in #theDress phenomenon, supporting the notion that the same trigger induces #theShoe.


From the raw bar to the bench: Bivalves as models for human health.
Bivalves, from raw oysters to steamed clams, are popular choices among seafood lovers and once limited to the coastal areas. The rapid growth of the aquaculture industry and improvement in the preservation and transport of seafood have enabled them to be readily available anywhere in the world. Over the years, oysters, mussels, scallops, and clams have been the focus of research for improving the production, managing resources, and investigating basic biological and ecological questions. During this decade, an impressive amount of information using high-throughput genomic, transcriptomic and proteomic technologies has been produced in various classes of the Mollusca group, and it is anticipated that basic and applied research will significantly benefit from this resource. One aspect that is also taking momentum is the use of bivalves as a model system for human health. In this review, we highlight some of the aspects of the biology of bivalves that have direct implications in human health including the shell formation, stem cells and cell differentiation, the ability to fight opportunistic and specific pathogens in the absence of adaptive immunity, as source of alternative drugs, mucosal immunity and, microbiome turnover, toxicology, and cancer research. There is still a long way to go; however, the next time you order a dozen oysters at your favorite raw bar, think about a tasty model organism that will not only please your palate but also help unlock multiple aspects of molluscan biology and improve human health.


Chlamydia psittaci Infection in nongastrointestinal extranodal MALT lymphomas and their precursor lesions.
Extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT) are associated with various infectious pathogens. We analyzed the presence of Chlamydia psittaci, Chlamydia pneumoniae, and Chlamydia trachomatis DNA in 47 nongastrointestinal and 14 gastrointestinal MALT lymphomas, 37 nonmalignant control samples, and 27 autoimmune precursor lesions by polymerase chain reaction amplification and direct sequencing. In 47 nongastrointestinal MALT lymphomas, 13 (28%) were positive for C psittaci DNA compared with 4 (11%) of 37 nonmalignant control samples (P = .09). C psittaci was detected at variable frequencies in MALT lymphomas of different sites: lung, 100% (5/5; P < .01); thyroid gland, 30% (3/10; P > .05); salivary gland, 13% (2/15; P > .05); ocular adnexa, 15% (2/13); and skin, 25% (1/4). Of 27 autoimmune precursor lesions (11 Hashimoto thyroiditis and 16 Sjögren syndrome), 11 (41%) contained C psittaci DNA. Only 1 (7%) of 14 gastrointestinal MALT lymphomas was positive for C psittaci. All specimens were negative for C trachomatis and C pneumoniae. Besides ocular adnexal lymphomas, C psittaci infection is associated with nongastrointestinal MALT lymphomas and autoimmune precursor lesions, suggesting possible involvement of C psittaci-induced antigenic-driven MALT lymphomagenesis.


Differential effects of gamma-aminobutyric acid (GABA)-elevating agents on the neuroleptic-induced activation of striatal tyrosine-hydroxylase: evidence that di-n-propylacetate augments GABAergic neurotransmission.
Di-n-propylacetate (DPA), in contrast to many other agents which elevate brain gamma-aminobutyric acid (GABA) content, appears to increase GABA selectively in a compartment that is associated with nerve terminals. In order to determine whether the DPA-induced increase in nerve-terminal GABA could augment GABAergic transmission in substantia nigra, we examined the ability of DPA to influence nigrostriatal dopamine function. For this purpose, the neuroleptic-induced activation of striatal tyrosine hydroxylase (TH) was selected as a model system. Neuroleptic drugs, such as haloperidol, cause an allosteric activation of striatal TH which can be measured in vitro as a decrease in the Km of TH for cofactor (2-amino-4-hydroxy-6,7-dimethyl-5,6,7,8-tetrahydropterine). This effect can be reversed by treatment with GABA-receptor agonists. We therefore examined the ability of DPA to reverse the activation of striatal TH induced by haloperidol. DPA was able to reverse the haloperidol-induced activation of striatal TH in doses which caused a 30 to 50% increase in GABA in substantia nigra. The action of DPA was completely antagonized by treatment with bicuculline, a GABA-receptor antagonist, indicating that the effect of DPA is mediated via GABA receptors. The effect of amino-oxyacetic acid was also examined, since our previous evidence suggested that the GABA increase after this agent was largely associated with compartments of GABA other than nerve terminals. Amino-oxyacetic acid was less effective than DPA in preventing the haloperidol-induced activation of TH, despite the fact that nigral GABA was increased by 30 to 100%.


The shallow cognitive map hypothesis: A hippocampal framework for thought disorder in schizophrenia.
Memories are not formed in isolation. They are associated and organized into relational knowledge structures that allow coherent thought. Failure to express such coherent thought is a key hallmark of Schizophrenia. Here we explore the hypothesis that thought disorder arises from disorganized Hippocampal cognitive maps. In doing so, we combine insights from two key lines of investigation, one concerning the neural signatures of cognitive mapping, and another that seeks to understand lower-level cellular mechanisms of cognition within a dynamical systems framework. Specifically, we propose that multiple distinct pathological pathways converge on the shallowing of Hippocampal attractors, giving rise to disorganized Hippocampal cognitive maps and driving conceptual disorganization. We discuss the available evidence at the computational, behavioural, network, and cellular levels. We also outline testable predictions from this framework, including how it could unify major chemical and psychological theories of schizophrenia and how it can provide a rationale for understanding the aetiology and treatment of the disease.


Neuropilar projections of the anterior gastric receptor neuron in the stomatogastric ganglion of the Jonah crab, Cancer borealis.
Sensory neurons provide important feedback to pattern-generating motor systems. In the crustacean stomatogastric nervous system (STNS), feedback from the anterior gastric receptor (AGR), a muscle receptor neuron, shapes the activity of motor circuits in the stomatogastric ganglion (STG) via polysynaptic pathways involving anterior ganglia. The AGR soma is located in the dorsal ventricular nerve posterior to the STG and it has been thought that its axon passes through the STG without making contacts. Using high-resolution confocal microscopy with dye-filled neurons, we show here that AGR from the crab Cancer borealis also has local projections within the STG and that these projections form candidate contact sites with STG motor neurons or with descending input fibers from other ganglia. We develop and exploit a new masking method that allows us to potentially separate presynaptic and postsynaptic staining of synaptic markers. The AGR processes in the STG show diversity in shape, number of branches and branching structure. The number of AGR projections in the STG ranges from one to three simple to multiply branched processes. The projections come in close contact with gastric motor neurons and descending neurons and may also be electrically coupled to other neurons of the STNS. Thus, in addition to well described long-loop pathways, it is possible that AGR is involved in integration and pattern regulation directly in the STG.


Intestinal microbiota influences clinical outcome and side effects of early breast cancer treatment.
The prognosis of early breast cancer (BC) relies on cell autonomous and immune parameters. The impact of the intestinal microbiome on clinical outcome has not yet been evaluated. Shotgun metagenomics was used to determine the composition of the fecal microbiota in 121 specimens from 76 early BC patients, 45 of whom were paired before and after chemotherapy. These patients were enrolled in the CANTO prospective study designed to record the side effects associated with the clinical management of BC. We analyzed associations between baseline or post-chemotherapy fecal microbiota and plasma metabolomics with BC prognosis, as well as with therapy-induced side effects. We examined the clinical relevance of these findings in immunocompetent mice colonized with BC patient microbiota that were subsequently challenged with histo-compatible mouse BC and chemotherapy. We conclude that specific gut commensals that are overabundant in BC patients compared with healthy individuals negatively impact BC prognosis, are modulated by chemotherapy, and may influence weight gain and neurological side effects of BC therapies. These findings obtained in adjuvant and neoadjuvant settings warrant prospective validation.


Self-Assembled Bioinspired Nanocomposites.
Bioinspired materials engineering impacts the design of advanced functional materials across many domains of sciences from wetting behavior to optical and mechanical materials. In all cases, the advances in understanding how biology uses hierarchical design to create failure and defect-tolerant materials with emergent properties lays the groundwork for engaging into these topics. Biological mechanical materials are particularly inspiring for their unique combinations of stiffness, strength, and toughness together with lightweightness, as assembled and grown in water from a limited set of building blocks at room temperature. Wood, nacre, crustacean cuticles, and spider silk serve as some examples, where the correct arrangement of constituents and balanced molecular energy dissipation mechanisms allows overcoming the shortcomings of the individual components and leads to synergistic materials performance beyond additive behavior. They constitute a paradigm for future structural materials engineering-in the formation process, the use of sustainable building blocks and energy-efficient pathways, as well as in the property profiles-that will in the long term allow for new classes of high-performance and lightweight structural materials needed to promote energy efficiency in mobile technologies.This Account summarizes our efforts of the past decade with respect to designing self-assembling bioinspired materials aiming for both mechanical high-performance structures and new types of multifunctional property profiles. The Account is set out to first give a definition of bioinspired nanocomposite materials and self-assembly therein, followed by an in-depth discussion on the understanding of mechanical performance and rational design to increase the mechanical performance. We place a particular emphasis on materials formed at high fractions of reinforcements and with tailor-made functional polymers using self-assembly to create highly ordered structures and elucidate in detail how the soft polymer phase needs to be designed in terms of thermomechanical properties and sacrificial supramolecular bonds. We focus on nanoscale reinforcements such as nanoclay and nanocellulose that lead to high contents of internal interfaces and intercalated polymer layers that experience nanoconfinement. Both aspects add fundamental challenges for macromolecular design of soft phases using precision polymer synthesis. We build upon those design criteria and further develop the concepts of adaptive bioinspired nanocomposites, whose properties are switchable from the outside using molecularly defined triggers with light. In a last section, we discuss how new types of functional properties, in particular flexible and transparent gas barrier materials or fire barrier materials, can be reached on the basis of the bioinspired nanocomposite design strategies. Additionally, we show new types of self-assembled photonic materials that can even be evolved into self-assembling lasers, hence moving the concept of mechanical nanocomposite design to other functionalities.The comparative discussion of different bioinspired nanocomposite architectures with nematic, fibrillar, and cholesteric structures, as based on different reinforcing nanoparticles, aims for a unified understanding of the design principles and shall aid researchers in the field in the more elaborate design of future bioinspired nanocomposite materials based on molecular control principles. We conclude by addressing challenges, in particular also the need for a transfer from fundamental molecular materials science into scalable engineering materials of technological and societal relevance.


HTLV-III/LAV-neutralizing antibodies to an E. coli-produced fragment of the virus envelope.
Immunization with either an Escherichia coli recombinant segment of the human T-cell lymphotropic virus (HTLV-III/LAV) envelope protein (gp 120) or with deglycosylated gp 120 envelope protein produced antibodies that neutralize HTLV-III/LAV infection in vitro. Virus neutralization titers of these antisera were equivalent to those obtained with purified native gp120 as immunogen. This localizes at least one class of neutralizing epitopes to the carboxyl-terminal half of the molecule. In addition, native gp120 prevented HTLV-III/LAV--mediated cell fusion, whereas the recombinant gp120 fragment did not. This shows that although glycosylation is not required for induction of neutralizing antibodies, it may be important for interaction with CD4, the virus receptor. A segment of the HTLV-III/LAV envelope produced in E. coli may be an important ingredient of a vaccine for acquired immune deficiency syndrome.


Dietary Patterns among Older People and the Associations with Social Environment and Individual Factors in Taiwan: A Multilevel Analysis.
Individual factors relating to dietary behaviors are widely explored. However, the effects of social environment on dietary patterns for the older people are less explored. The purpose of this study was to identify dietary patterns among older people in Taiwan and to examine the relationship of dietary patterns with social environment and individual factors. The current study used the 2013-2016 Nutrition and Health Survey in Taiwan. The sample was representative at the national and city levels. Only those who were aged 55 years old and above were included for analysis (n = 2922); the mean age of the participants was 68.62 (SD = 8.76). The city-level data, including population characteristics, food availability, and age-friendly city indicators, were obtained from the open data and survey report of government. Three dietary patterns were identified: high protein-vegetable (41.6%), high sweets and low protein-vegetables (37.9%), and high viscera and fats (20.5%). The results of multilevel multinomial logistic regressions showed that marital status, economic status, education, drinking alcohol, dietary belief, living a the city with more food availability, and bus accessibility were related to dietary patterns. Dietary patterns are related to the individual-level factors and social environment. Healthy dietary beliefs and age-friendly environments are beneficial to promoting healthy dietary patterns.


Modeling of hemodialysis operation.
In this study, a theoretical model was developed to predict the solute concentrations in patients' blood and optimize the efficiency of the hemodialysis operation. The model takes into account simultaneous mass and momentum transfer on the blood side both in radial and axial directions. A key component of the model is the incorporation of the protein adsorption on the inner surface of the membrane. The validity of the model was confirmed with the experimental data available in the literature for two different types of hemodiafilter. To illustrate the importance of including the radial concentration gradients and protein adsorption kinetics in the model, the experimental data were predicted with and without consideration of these effects. The results have shown that assuming uniform concentration in the radial direction or neglecting protein adsorption on the inner surface of the membrane leads to higher error in predicting the experimental data. In addition, significant error can be introduced in the calculation of the dialysis time if protein adsorption is not considered.


Targeting levels or oligomerization of nucleophosmin 1 induces differentiation and loss of survival of human AML cells with mutant NPM1.
Nucleophosmin 1 (NPM1) is an oligomeric, nucleolar phosphoprotein that functions as a molecular chaperone for both proteins and nucleic acids. NPM1 is mutated in approximately one-third of patients with AML. The mutant NPM1c+ contains a 4-base insert that results in extra C-terminal residues encoding a nuclear export signal, which causes NPM1c+ to be localized in the cytoplasm. Here, we determined the effects of targeting NPM1 in cultured and primary AML cells. Treatment with siRNA to NPM1 induced p53 and p21, decreased the percentage of cells in S-phase of the cell cycle, as well as induced differentiation of the AML OCI-AML3 cells that express both NPMc+ and unmutated NPM1. Notably, knockdown of NPM1 by shRNA abolished lethal AML phenotype induced by OCI-AML3 cells in NOD/SCID mice. Knockdown of NPM1 also sensitized OCI-AML3 to all-trans retinoic acid (ATRA) and cytarabine. Inhibition of NPM1 oligomerization by NSC348884 induced apoptosis and sensitized OCI-AML3 and primary AML cells expressing NPM1c+ to ATRA. This effect was significantly less in AML cells coexpressing FLT3-ITD, or in AML or normal CD34+ progenitor cells expressing wild-type NPM1. Thus, attenuating levels or oligomerization of NPM1 selectively induces apoptosis and sensitizes NPM1c+ expressing AML cells to treatment with ATRA and cytarabine.


Limit cycle models for circadian rhythms based on transcriptional regulation in Drosophila and Neurospora.
We examine theoretical models for circadian oscillations based on transcriptional regulation in Drosophila and Neurospora. For Drosophila, the molecular model is based on the negative feedback exerted on the expression of the per and tim genes by the complex formed between the PER and TIM proteins. For Neurospora, similarly, the model relies on the feedback exerted on the expression of the frq gene by its protein product FRQ. In both models, sustained rhythmic variations in protein and mRNA levels occur in continuous darkness, in the form of limit cycle oscillations. The effect of light on circadian rhythms is taken into account in the models by considering that it triggers degradation of the TIM protein in Drosophila, and frq transcription in Neurospora. When incorporating the control exerted by light at the molecular level, we show that the models can account for the entrainment of circadian rhythms by light-dark cycles and for the damping of the oscillations in constant light, though such damping occurs more readily in the Drosophila model. The models account for the phase shifts induced by light pulses and allow the construction of phase response curves. These compare well with experimental results obtained in Drosophila. The model for Drosophila shows that when applied at the appropriate phase, light pulses of appropriate duration and magnitude can permanently or transiently suppress circadian rhythmicity. We investigate the effects of the magnitude of light-induced changes on oscillatory behavior. Finally, we discuss the common and distinctive features of circadian oscillations in the two organisms.


Forced expression of dystrophin deletion constructs reveals structure-function correlations.
Dystrophin plays an important role in skeletal muscle by linking the cytoskeleton and the extracellular matrix. The amino terminus of dystrophin binds to actin and possibly other components of the subsarcolemmal cytoskeleton, while the carboxy terminus associates with a group of integral and peripheral membrane proteins and glycoproteins that are collectively known as the dystrophin-associated protein (DAP) complex. We have generated transgenic/mdx mice expressing "full-length" dystrophin constructs, but with consecutive deletions within the COOH-terminal domains. These mice have enabled analysis of the interaction between dystrophin and members of the DAP complex and the effects that perturbing these associations have on the dystrophic process. Deletions within the cysteine-rich region disrupt the interaction between dystrophin and the DAP complex, leading to a severe dystrophic pathology. These deletions remove the beta-dystroglycan-binding site, which leads to a parallel loss of both beta-dystroglycan and the sarcoglycan complex from the sarcolemma. In contrast, deletion of the alternatively spliced domain and the extreme COOH terminus has no apparent effect on the function of dystrophin when expressed at normal levels. The proteins resulting from these latter two deletions supported formation of a completely normal DAP complex, and their expression was associated with normal muscle morphology in mdx mice. These data indicate that the cysteine-rich domain is critical for functional activity, presumably by mediating a direct interaction with beta-dystroglycan. However, the remainder of the COOH terminus is not required for assembly of the DAP complex.


Computational Prediction of Electron Ionization Mass Spectra to Assist in GC/MS Compound Identification.
We describe a tool, competitive fragmentation modeling for electron ionization (CFM-EI) that, given a chemical structure (e.g., in SMILES or InChI format), computationally predicts an electron ionization mass spectrum (EI-MS) (i.e., the type of mass spectrum commonly generated by gas chromatography mass spectrometry). The predicted spectra produced by this tool can be used for putative compound identification, complementing measured spectra in reference databases by expanding the range of compounds able to be considered when availability of measured spectra is limited. The tool extends CFM-ESI, a recently developed method for computational prediction of electrospray tandem mass spectra (ESI-MS/MS), but unlike CFM-ESI, CFM-EI can handle odd-electron ions and isotopes and incorporates an artificial neural network. Tests on EI-MS data from the NIST database demonstrate that CFM-EI is able to model fragmentation likelihoods in low-resolution EI-MS data, producing predicted spectra whose dot product scores are significantly better than full enumeration "bar-code" spectra. CFM-EI also outperformed previously reported results for MetFrag, MOLGEN-MS, and Mass Frontier on one compound identification task. It also outperformed MetFrag in a range of other compound identification tasks involving a much larger data set, containing both derivatized and nonderivatized compounds. While replicate EI-MS measurements of chemical standards are still a more accurate point of comparison, CFM-EI's predictions provide a much-needed alternative when no reference standard is available for measurement. CFM-EI is available at https://sourceforge.net/projects/cfm-id/ for download and http://cfmid.wishartlab.com as a web service.


Molecular mechanisms of fluoroquinolone resistance.
Fluoroquinolones have a broad spectrum of activity for complicated urinary tract infections, gastrointestinal infections, respiratory tract infections, sexually transmitted diseases, and chronic osteomyelitis. Since fluoroquinolones are excellent antibiotics for a number of clinical indications, their consumption has increased rapidly, both in human medicine and in food animals. Resistance to fluoroquinolones is chromosomal mediated, involving mutations either in the target genes including DNA gyrase (gyrA or gyrB) and topoisomerase IV (parC or parE), or in the regulatory factors controlling bacterial permeability or the efflux capacity of the bacteria. This review focuses on mechanisms of fluoroquinolone resistance, including known and proposed molecular mechanisms. This review also discuses the clinical impact of fluoroquinolone-resistant bacteria.


Comparative long-term toxicity of Libby amphibole and amosite asbestos in rats after single or multiple intratracheal exposures.
In former mine workers of Libby, MT, exposure to amphibole-containing vermiculite was linked to increased rates of asbestosis, lung cancer, and mesothelioma. Although many studies showed adverse effects following exposure to Libby amphibole (LA; a mixture of winchite, richterite, and tremolite), little is known regarding the relative toxicity of LA compared to regulated asbestos, or regarding the risks associated with acute high-dose exposures relative to repeated low-dose exposures. In this study, pulmonary function, inflammation, and pathology were assessed after single or multiple intratracheal (IT) exposures of LA or a well-characterized amosite (AM) control fiber with equivalent fiber characteristics. Male F344 rats were exposed to an equivalent total mass dose (0.15, 0.5, 1.5, or 5 mg/rat) of LA or AM administered either as a single IT instillation, or as multiple IT instillations given every other week over a 13-wk period, and necropsied up to 20 mo after the initial IT. When comparing the two fiber types, in both studies LA resulted in greater acute neutrophilic inflammation and cellular toxicity than equal doses of AM, but long-term histopathological changes were approximately equivalent between fibers, suggesting that LA is at least as toxic as AM. In addition, although no dose-response relationship was discerned, mesothelioma or lung carcinomas were found after exposure to low and high dose levels of LA or AM in both studies. Conversely, when comparing studies, an equal mass dose given over multiple exposures instead of a single bolus resulted in greater chronic pathological changes in lung at lower doses, despite the initially weaker acute inflammatory response. Overall, these results suggest that there is a possibility of greater long-term pathological changes with repeated lower LA dose exposures, which more accurately simulates chronic environmental exposures.


A task dependent change in the medium latency component of the soleus stretch reflex.
In comparison to the H-reflex, the task dependency of the human stretch reflex during locomotive and postural tasks has not received a great deal of attention in the literature. The few studies on reflex task dependency that have been performed to date have concentrated on either the group Ia mediated H-reflex or the short latency stretch reflex. In the present study the medium latency component of a mechanically evoked stretch reflex is investigated during walking, pedalling, and sitting. Stretch reflexes were evoked in the soleus muscle using dorsiflexion perturbations generated with a portable stretching device. Perturbations of equal amplitude and velocity (8 deg, 300 deg/s) were presented to 16 healthy subjects while they walked on a treadmill and pedalled a cycle ergometer. For eight of these subjects, an additional set of data was collected as they sat on the ergometer holding a steady posture. Perturbations were presented in the early to mid stance phase of walking and the downstroke of the pedal cycle. During all three conditions, the background soleus muscle activity was matched. The short (SLR) and medium (MLR) components of the soleus reflex responses were quantified by calculating the area of each burst in a 15-ms window centred on the peak of the respective burst. In addition, the stretch velocity-stretch reflex input-output curve was examined for the two locomotion tasks over a range of velocities from 100 to 400 deg/s. Peak latencies for the two reflex responses were observed at 52+/-5/77+/-6 ms (SLR/MLR) for walking, 51+/-3/76+/-6 ms (SLR/MLR) for pedalling, and 50+/-3/76+/-7 ms for sitting. A statistically significant increase in the magnitude of the MLR was observed during walking compared with pedalling and sitting ( P=0.007), whereas no difference in magnitude was observed between the three tasks for the SLR ( P=0.616). Furthermore, no difference was observed in the stretch velocity-stretch reflex input-output relationship between walking and pedalling. It is suggested that the medium component of the stretch reflex response is modulated to provide increased control for the postural demands of walking.


Does citation matter? Research citation in policy documents as an indicator of research impact - an Australian obesity policy case-study.
Citation of research in policy documents has been suggested as an indicator of the potential longer-term impacts of research. We investigated the use of research citations in childhood obesity prevention policy documents from New South Wales (NSW), Australia, considering the feasibility and value of using research citation as a proxy measure of research impact. We examined childhood obesity policy documents produced between 2000 and 2015, extracting childhood obesity-related references and coding these according to reference type, geographical origin and type of research. A content analysis of the policy documents examined where and how research was cited in the documents and the context of citation for individual research publications. Over a quarter (28%) of the policy documents (n = 86) were not publicly available, almost two-thirds (63%) contained references, half (47%) cited obesity-related research and over a third (41%) of those containing references used unorthodox referencing styles, making reference extraction laborious. No patterns, in terms of the types of documents more likely to cite research, were observed and the number of obesity research publications cited per document was highly variable. In total, 263 peer-reviewed and 94 non-peer-reviewed obesity research publications were cited. Research was most commonly cited to support a policy argument or choice of solution. However, it was not always possible to determine how or why individual publications were cited or whether the cited research itself had influenced the policy process. Content analysis identified circumstances where research was mentioned or considered, but not directly cited. Citation of research in policy documents in this case did not always provide evidence that the cited research had influenced the policy process, only that it was accessible and relevant to the content of the policy document. Research citation across these public health policy documents varied greatly and is unlikely to be an accurate reflection of actual research use by the policy agencies involved. The links between citation and impact may be more easily drawn in specific policy areas or types of documents (e.g. clinical guidelines), where research appraisal feeds directly into policy recommendations.


Assessment of nasal patency after rhinoplasty through the Glatzel mirror.
OBJECTIVE evaluation of nasal function is a constant challenge for plastic surgeons, otolaryngologists, and allergists. The modified Glatzel mirror can evaluate nasal expiratory flow; however, there is little information on this method and its use in the measurement of nasal patency after surgical procedures. To compare, in a prospective study, the functional results before and after cosmetic rhinoplasty and evaluate the use of the Glatzel mirror as an objective method to assess nasal patency. To achieve this objective, we analyzed the functional results of surgery through a subjective questionnaire and objective evaluation through a modified Glatzel mirror, and evaluated the correlation between the 2 methods. Twenty patients (14 women and 6 men) underwent aesthetic rhinoplasty using spreader grafts. Pre- and postoperative evaluation (90-120 days) included a respiratory quality score (subjective) and modified Glatzel mirror test (objective). Subsequently, the Spearman test was used to compare the pre- and postoperative subjective and objective data. The subjective evaluation demonstrated a statistical difference between pre- and postoperative scores (8 ± 2 and 9.4 ± 0.7, P ≤ 0.001). There was no statistical difference in mean nasal patency by modified Glatzel mirror. No statistically significant correlation was observed when comparing the modified Glatzel mirror values with the subjective scores reported by patients pre- or postoperatively. The Glatzel method lacks sensitivity in detecting patient-reported improvements in breathing following rhinoplasty. This suggests that the method is a poor assessment tool to detect small, post-surgical changes in the nasal airways.


Roles and challenges of outreach workers in HIV clinical and support programs serving young racial/ethnic minority men who have sex with men.
The federal government has established rapid identification, linkage, and engagement in medical care of HIV-positive individuals as a high priority. Outreach workers and other linkage coordinators are identified as key personnel in implementing this policy. Young racial/ethnic minority men who have sex with men (MSM) have relatively high and growing rates of HIV infection and would benefit from the services of outreach workers. In this article, we describe the characteristics of outreach workers employed by eight demonstration sites participating in the federal Special Projects of National Significance (SPNS) Young MSM of Color Initiative, the linkage and retention models used by the sites, and the number of outreach/ linkage contacts and individuals referred to HIV care. We summarize rates of retention of outreach workers in employment, factors associated with worker turnover, and costs associated with their replacement. We also summarize the experiences of demonstration sites in employing and retaining outreach workers and improving their performance. The insights of outreach workers are reported regarding the challenges they experienced while conducting outreach. Recommendations from demonstration site project managers and outreach workers are offered to improve workplace performance and job retention. Outreach and retention strategies, as well as lessons learned in employing outreach workers, are useful to programs serving young racial/ethnic minority MSM and other HIV-positive groups.


VASA: Interactive Computational Steering of Large Asynchronous Simulation Pipelines for Societal Infrastructure.
We present VASA, a visual analytics platform consisting of a desktop application, a component model, and a suite of distributed simulation components for modeling the impact of societal threats such as weather, food contamination, and traffic on critical infrastructure such as supply chains, road networks, and power grids. Each component encapsulates a high-fidelity simulation model that together form an asynchronous simulation pipeline: a system of systems of individual simulations with a common data and parameter exchange format. At the heart of VASA is the Workbench, a visual analytics application providing three distinct features: (1) low-fidelity approximations of the distributed simulation components using local simulation proxies to enable analysts to interactively configure a simulation run; (2) computational steering mechanisms to manage the execution of individual simulation components; and (3) spatiotemporal and interactive methods to explore the combined results of a simulation run. We showcase the utility of the platform using examples involving supply chains during a hurricane as well as food contamination in a fast food restaurant chain.


Modified Gaussian approach for the design of optical fiber couplers of arbitrary core shapes.
Many fiber devices, e.g. fiber couplers, rely on the cladding evanescent field for their operation. We present a new method for determining the approximate fundamental mode fields, with particular reference to cladding field applications. In our method, by introducing a field which is accurate both near to and far from the core axis, coupling parameters in fiber couplers can be obtained in a simple form. We apply this to studies of couplers consisting of two identical cores of arbitrary shape. We have compared the results from the new approximation with those from the usual Gaussian in circular core cases where exact solutions can be found and have shown that the new approximation can give more accurate propagation constants and, especially, fundamental mode fields. The evanescent behavior of these fields is directly related to the coupling features of a fiber coupler. In particular, we apply this new method to twin elliptic core fibers to quantify their polarization transmitting and polarization coupling characteristics. Up to now, as far as we know, no method has seemed appropriate to handle this system. Design features of birefringent and polarization coupling of these fibers for device applications are also discussed.


Isolation and characterization of the progenitor cells from the blastema tissue formed at experimentally-created rabbit ear hole.
Objective(s) : Throughout evolution, mammalians have increasingly lost their ability to regenerate structures however rabbits are exceptional since they develop a blastema in their ear wound for regeneration purposes. Blastema consists of a group of undifferentiated cells capable of dividing and differentiating into the ear tissue. The objective of the present study is to isolate, culture expand, and characterize blastema progenitor cells in terms of their in vitro differentiation capacity. Five New Zealand white male rabbits were used in the present study. Using a punching apparatus, a 4-mm hole was created in the animal ears. Following 4 days, the blastema ring which was created in the periphery of primary hole in the ears was removed and cultivated. The cells migrated from the blastema were expanded through 3 successive subcultures and characterized in terms of their potential differentiation, growth characteristics, and culture requirements. The primary cultures tended to be morphologically heterogeneous having spindly-shaped fibroblast-like cells as well as flattened cells. Fibroblast-like cells survived and dominated the cultures. These cells tended to have the osteogenic, chondrogenic, and adipogenic differentiation potentials. They were highly colonogenic and maximum proliferation was achieved when the cells were plated at density of 100 cells/cm2 in a medium which contained 10% fetal bovine serum (FBS). Taken together, blastema tissue-derived stem cells from rabbit ear are of mesenchymal stem cell-like population. Studies similar to this will assist scientist better understanding the nature of blastema tissue formed at rabbit ear to regenerate the wound.


Is thoracic spine posture associated with shoulder pain, range of motion and function? A systematic review.
Excessive thoracic kyphosis is considered a predisposing factor for shoulder pain, though there is uncertainty about the nature of the relationship between shoulder pain and thoracic spine posture. The aim of this systematic review was to investigate the relationship between thoracic kyphosis and shoulder pain, shoulder range of motion (ROM) and function. Two reviewers independently searched eight electronic databases and identified relevant studies by applying eligibility criteria. Sources of bias were assessed independently by two reviewers using a previously validated tool (Ijaz et al., 2013). Data were synthesised using a level of evidence approach (van Tulder et al., 2003). Ten studies were included. Four studies were rated as low risk of bias, three at moderate risk of bias and three at high risk of bias. There is a moderate level of evidence of no significant difference in thoracic kyphosis between groups with and without shoulder pain. One study at high risk of bias demonstrated significantly greater thoracic kyphosis in people with shoulder pain (p < 0.05). There is a strong level of evidence that maximum shoulder ROM is greater in erect postures compared to slouched postures (p < 0.001), in people with and without shoulder pain. Thoracic kyphosis may not be an important contributor to the development of shoulder pain. While there is evidence that reducing thoracic kyphosis facilitates greater shoulder ROM, this is based on single-session studies whose long-term clinical relevance is unclear. Higher quality research is warranted to fully explore the role of thoracic posture in shoulder pain.


Bilateral pelvi-ureteric junction obstruction: our experience in a developing country.
Bilateral pelvi-ureteric junction (PUJ) obstruction is rare and causes high morbidity and mortality. Recent advances have led to its diagnosis and management in the perinatal period. However, open surgery is still the mainstay of treatment in less endowed nations where late presentation is the norm. All patients with PUJ obstruction diagnosed and managed at the University of Maiduguri Teaching Hospital between January 2006 and December 2011 were retrospectively reviewed. All had open surgery and all repairs were stented with double J stents or appropriate size feeding tube. A total of 18 patients were analyzed, 11 males and 7 females with a ratio of 1.57:1 and mean age of 27.5 years (age range 2-38). The main clinical features were loin pain (72.22%) and fever (72.22%); while the main complications at presentation were hydronephrosis (55.56%), impaired renal function (61.11%) and pyelonephritis (50%). The causes of obstruction were mainly congenital (50.0%) and due to schistosomal fibrosis/stricture (22.2%). Preliminary double J stents, tube nephrostomies and hemodialysis were used to recover renal function before surgery. Anderson-Hynes (41.7%) and Heineke-Mirhulicz (19.4%) pyeloplasty were the main procedures performed. The main post-operative complications were urinary tract infections (67.67%) and leakage (11.11%). The mean duration of symptoms was 23.72 months and the mean hospital stay was 13 days. The mortality rate was 5.56%. Bilateral PUJ obstruction is uncommon in Maiduguri, with congenital causes and schistosomal fibrosis as the most common etiologies. Aggressive treatment aimed at recovering renal function is necessary before open pyeloplasty if morbidity and mortality is to be reduced. Open pyeloplasty remained the best treatment option with favorable outcome.


Role of the parietooccipital fissure and its implications in the pathophysiology of posterior medial temporal gliomas.
The parietooccipital fissure is an anatomical landmark that divides the temporal, occipital, and parietal lobes. More than 40% of gliomas are located in these three lobes, and the temporal lobe is the most common location. The parietooccipital fissure is located just posterior to the medial temporal lobe, but little is known about the clinical significance of this fissure in gliomas. The authors investigated the anatomical correlations between the parietooccipital fissure and posterior medial temporal gliomas to reveal the radiological features and unique invasion patterns of these gliomas. The authors retrospectively reviewed records of all posterior medial temporal glioma patients treated at their institutions and examined the parietooccipital fissure. To clarify how the surrounding structures were invaded in each case, the authors categorized tumor invasion as being toward the parietal lobe, occipital lobe, isthmus of the cingulate gyrus, insula/basal ganglia, or splenium of the corpus callosum. DSI Studio was used to visualize the fiber tractography running through the posterior medial temporal lobe. Twenty-four patients with posterior medial temporal gliomas were identified. All patients presented with a parietooccipital fissure as an uninterrupted straight sulcus and as the posterior border of the tumor. Invasion direction was toward the parietal lobe in 13 patients, the occipital lobe in 4 patients, the isthmus of the cingulate gyrus in 19 patients, the insula/basal ganglia in 3 patients, and the splenium of the corpus callosum in 8 patients. Although the isthmus of the cingulate gyrus and the occipital lobe are located just posterior to the posterior medial temporal lobe, there was a significantly greater preponderance of invasion toward the isthmus of the cingulate gyrus than toward the occipital lobe (p = 0.00030, McNemar test). Based on Schramm's classification for the medial temporal tumors, 4 patients had type A and 20 patients had type D tumors. The parietooccipital fissure determined the posterior border of the tumors, resulting in a unique and identical radiological feature. Diffusion spectrum imaging (DSI) tractography indicated that the fibers running through the posterior medial temporal lobe toward the occipital lobe had to detour laterally around the bottom of the parietooccipital fissure. Posterior medial temporal gliomas present identical invasion patterns, resulting in unique radiological features that are strongly affected by the parietooccipital fissure. The parietooccipital fissure is a key anatomical landmark for understanding the complex infiltrating architecture of posterior medial temporal gliomas.


Crystal Structure of the Homing Endonuclease I-CvuI Provides a New Template for Genome Modification.
Homing endonucleases recognize and generate a DNA double-strand break, which has been used to promote gene targeting. These enzymes recognize long DNA stretches; they are highly sequence-specific enzymes and display a very low frequency of cleavage even in complete genomes. Although a large number of homing endonucleases have been identified, the landscape of possible target sequences is still very limited to cover the complexity of the whole eukaryotic genome. Therefore, the finding and molecular analysis of homing endonucleases identified but not yet characterized may widen the landscape of possible target sequences. The previous characterization of protein-DNA interaction before the engineering of new homing endonucleases is essential for further enzyme modification. Here we report the crystal structure of I-CvuI in complex with its target DNA and with the target DNA of I-CreI, a homologue enzyme widely used in genome engineering. To characterize the enzyme cleavage mechanism, we have solved the I-CvuI DNA structures in the presence of non-catalytic (Ca(2+)) and catalytic ions (Mg(2+)). We have also analyzed the metal dependence of DNA cleavage using Mg(2+) ions at different concentrations ranging from non-cleavable to cleavable concentrations obtained from in vitro cleavage experiments. The structure of I-CvuI homing endonuclease expands the current repertoire for engineering custom specificities, both by itself as a new scaffold alone and in hybrid constructs with other related homing endonucleases or other DNA-binding protein templates.


Inhibition of tubulin polymerization by select alkenyldiarylmethanes.
During studies on the alkenyldiarylmethane (ADAM) class of non-nucleoside reverse transcriptase inhibitors (NNRTIs), analogues were discovered that exhibit low micromolar and submicromolar cytotoxicities. Since the ADAMs are structurally related to the tubulin polymerization inhibitor CC-5079, a set of 14 ADAMs were tested for inhibition of tubulin polymerization in an attempt to identify the biological target responsible for their cytotoxicity. The results indicate that, overall, the ADAMs are poor inhibitors of tubulin polymerization. However, the two most cytotoxic compounds, 15 and 16, are in fact active as inhibitors of tubulin assembly with IC(50) values of 3.7+/-0.3 and 2.8+/-0.2 microM, respectively, and they both inhibit the binding of colchicine to tubulin. Both compounds were investigated for anticancer activity in the National Cancer Institute's panel of 60 human cancer cell lines, and both compounds consistently displayed submicromolar cytotoxicities with mean-graph midpoint (MGM) values of 0.31+/-0.08 and 0.47+/-0.09 microM, respectively.


Reconsidering GHB: orphan drug or new model antidepressant?
For six decades, the principal mode of action of antidepressant drugs is the inhibition of monoamine re-uptake from the synaptic cleft. Tricyclic antidepressants, selective serotonin re-uptake inhibitors (SSRIs) and the new generation of dual antidepressants all exert their antidepressant effects by this mechanism. In the early days of the monoaminergic era, other efforts have been made to ameliorate the symptoms of depression by pharmacological means. The gamma-aminobutyric acid (GABA) system was and possibly still is one of the main alternative drug targets. Gammahydroxybutyrate (GHB) was developed as an orally active GABA analogue. It was tested in animal models of depression and human studies. The effects on sleep, agitation, anhedonia and depression were promising. However, the rise of benzodiazepines and tricyclic antidepressants brought GHB out of the scope of possible treatment alternatives. GHB is a GABA(B) and GHB receptor agonist with a unique spectrum of behavioural, neuroendocrine and sleep effects, and improves daytime sleepiness in various disorders such as narcolepsy, Parkinson's disease and fibromyalgia. Although it was banned from the US market at the end of the 1990s because of its abuse and overdose potential, it later was approved for the treatment of narcolepsy. New research methods and an extended view on other neurotransmitter systems as possible treatment targets of antidepressant treatment brought GHB back to the scene. This article discusses the unique neurobiological effects of GHB, its misuse potential and possible role as a model substance for the development of novel pharmacological treatment strategies in depressive disorders.


A post-hoc subgroup analysis of outcomes in the first phase III clinical study of edaravone (MCI-186) in amyotrophic lateral sclerosis.
Our first phase III study failed to demonstrate efficacy of edaravone for amyotrophic lateral sclerosis (ALS) compared to placebo. Here, we performed post-hoc subgroup analysis to identify a subgroup in which edaravone might be expected to show efficacy. We focussed on two newly defined subgroups, EESP and dpEESP2y. The EESP was defined as the efficacy-expected subpopulation with % forced vital capacity of ≥80%, and ≥2 points for all item scores in the revised ALS functional rating scale (ALSFRS-R) score before treatment. The dpEESP2y was defined as the greater-efficacy-expected subpopulation within EESP having a diagnosis of 'definite' or 'probable' ALS according to the El Escorial revised Airlie House diagnostic criteria and onset of disease within two years. The primary endpoint of the post-hoc analysis was the change in the ALSFRS-R score during the 24-week treatment period. The intergroup differences of the least-squares mean change in the ALSFRS-R score ± standard error during treatment were 0.65 ± 0.78 (p = 0.4108) in the full analysis set, 2.20 ± 1.03 (p = 0.0360) in the EESP, and 3.01 ± 1.33 (p = 0.0270) in the dpEESP2y. Edaravone exhibited efficacy in the dpEESP2y subgroup. A further clinical study in patients meeting dpEESP2y criteria is warranted.


Stressful life events, parental psychosocial factors, and glycemic management in school-aged children during the 1 year follow-up of new-onset type 1 diabetes.
To monitor occurrence of stressful life events, assess correlations with family functioning and parental psychosocial measures, and examine the impact of stressful life events on diabetes management in the first year after diagnosis of type 1 diabetes (T1D) in children using a mixed methods design. In a prospective study of 5- to 9-year-olds with recent-onset T1D (mean age 7.4 ± 1.3 years, T1D duration 4.7 ± 3.3 months), we monitored glycated hemoglobin A1c (HbA1c), income, job status, family health, and marital status at baseline and every 3 months up to 1 year. We measured coping, parental depression, and diabetes family conflict at baseline. Of 128 families, 53.9% (n = 69) reported 1+ stressful event, with 25.8% reporting income change (n = 33) during this period, 23.4% additional family health changes (n = 30), 22.7% job changes (n = 29), 21.9% changes in child's school (n = 28), and 3.9% changes in marital status (n = 5). Baseline active avoidance coping, parental depression, and diabetes family conflict correlated with a higher number of stressful life events (r = 0.239, P < .01; r = 0.197, P < .05; r = 0.225, P < .01, respectively). There were also cross-sectional associations between HbA1c and income decrease, school change, and job change at various time points in the study. Families can experience concurrent life stressors during the first year of T1D, which relate to coping, depression, and conflict. Consistent with existing literature, stressful life events relate to glycemic management. Future research should explore the individual's or parent's perception of stress and ways that diabetes centers can effectively assist families of youth with T1D and concurrent life stressors.


Chylous ascites in infants and children.
Chylous ascites in infants and children has been the subject of 35 articles in the English language literature during the past 30 years. Analysis of the cases of 58 patients reveals that chylous ascites has been reported twice as frequently in infants as in older children, but that the clinical presentations, essentials of diagnosis, treatment alternatives, and mortality rates have been otherwise remarkably similar. Two thirds of patients treated without operation were cured, half of them within the first month of therapy. Even though the documented experience with total parenteral nutrition in infants and children with chylous ascites is remarkably scant, parenteral nutritional support appears to have decreased the hazard of medical therapy by maintaining an adequate nutritional intake while eliminating obligate losses consequent to repeated paracentesis. Patients in whom chylous ascites recurs, after resumption of a regular diet, should undergo surgical exploration, according to a defined strategy that includes visualization of the retroperitoneal origin of the superior mesenteric artery.


Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML15 trial.
Treatment outcomes in younger patients with acute myeloid leukemia (AML) have improved, but optimization and new combinations are needed. We assess three combinations in induction and consolidation. Younger untreated patients with AML (median age, 49 years; range, 0 to 73 years) were randomly allocated to two induction courses of daunorubicin and cytarabine (DA) with or without etoposide (ADE; n = 1983) or ADE versus fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-Ida; n = 1268), and to amsacrine, cytarabine, etoposide, and then mitoxantrone/cytarabine (MACE-MidAC) or high-dose cytarabine (n = 1,445) 3 g/m(2) or 1.5 g/m(2) (n = 657) in consolidation, and finally to a fifth course (cytarabine) or not (n = 227). Overall remission rates were similar for DA versus ADE (84% v 86%; P = .14) and ADE versus FLAG-Ida (86% v 85%; P = .7), with more course 1 remissions after FLAG-Ida (77%) reducing relapse (38% v 55%; P < .001) and improving relapse-free survival (45% v 34%; P = .01), overall and in subgroups, but with increased myelosuppression, reducing participation in the consolidation randomization. Overall outcomes were similar between MACE/MidAc and high-dose cytarabine (1.5/3.0 g/m(2)), but cytarabine required less supportive care. MACE/MidAc was superior for high-risk patients. A fifth course provided no benefit. The outcome for recipients of only two FLAG-Ida courses were not different from that with DA/ADE with consolidation. FLAG-Ida is an effective remission induction treatment, with a high complete remission rate after course 1 and reduced relapse. Consolidation with MACE/MidAc is similar overall to high-dose cytarabine, but superior in high-risk patients. Cytarabine at 1.5 g/m(2) is equivalent to a 3 g/m(2) dose. A fifth course is unnecessary. In patients receiving FLAG-Ida (two courses) and cytarabine (two courses), 8-year survival was 63% for patients with intermediate-risk and 95% for those with favorable-risk disease.


On the uncertainty of interdisciplinarity measurements due to incomplete bibliographic data.
The accuracy of interdisciplinarity measurements is directly related to the quality of the underlying bibliographic data. Existing indicators of interdisciplinarity are not capable of reflecting the inaccuracies introduced by incorrect and incomplete records because correct and complete bibliographic data can rarely be obtained. This is the case for the Rao-Stirling index, which cannot handle references that are not categorized into disciplinary fields. We introduce a method that addresses this problem. It extends the Rao-Stirling index to acknowledge missing data by calculating its interval of uncertainty using computational optimization. The evaluation of our method indicates that the uncertainty interval is not only useful for estimating the inaccuracy of interdisciplinarity measurements, but it also delivers slightly more accurate aggregated interdisciplinarity measurements than the Rao-Stirling index.


The food intake-suppressive effects of glucagon-like peptide-1 receptor signaling in the ventral tegmental area are mediated by AMPA/kainate receptors.
Glucagon-like peptide-1 receptor (GLP-1R) activation in the ventral tegmental area (VTA) is physiologically relevant for the control of palatable food intake. Here, we tested whether the food intake-suppressive effects of VTA GLP-1R activation are mediated by glutamatergic signaling within the VTA. Intra-VTA injections of the GLP-1R agonist exendin-4 (Ex-4) reduced palatable high-fat food intake in rats primarily by reducing meal size; these effects were mediated in part via glutamatergic AMPA/kainate but not NMDA receptor signaling. Additional behavioral data indicated that GLP-1R expressed specifically within the VTA can partially mediate the intake- and body weight-suppressive effects of systemically administered Ex-4, offering the intriguing possibility that this receptor population may be clinically relevant for food intake control. Intra-VTA Ex-4 rapidly increased tyrosine hydroxylase levels within the VTA, suggesting that GLP-1R activation modulates VTA dopaminergic signaling. Further evidence for this hypothesis was provided by electrophysiological data showing that Ex-4 increased the frequency of AMPA-mediated currents and reduced the paired/pulse ratio in VTA dopamine neurons. Together, these data provide novel mechanisms by which GLP-1R agonists in the mesolimbic reward system control for palatable food intake.


Autologous Schwann cells drive regeneration through a 6-cm autogenous venous nerve conduit.
Peripheral nerve regeneration is a complex series of events, involving bi-directional interactions between regenerating axons and Schwann cells. These authors have demonstrated in their laboratory that nerves will regenerate through a 3-cm autogenous venous nerve conduit (AVNC) in an animal model and, with Dr. David Chiu, a similar distance in the human. They have shown that the upper limit of nerve regeneration in an empty AVNC was 3 cm, with no evidence of nerve growth at the 6-cm mark (no-growth model). Most recently, they have demonstrated rapid growth at 1 month in a 3-cm AVNC filled with Schwann cells, compared to poor-to-no-regrowth at 1 month in controls. While, in theory, Schwann-cell-derived growth factor should be sufficient to supplant the requirement for Schwann cells, in practice, therapies with growth factors have failed in clinical trials, with some resulting in severe morbidity and mortality for the subjects. The present study showed excellent nerve regeneration through a 6-cm AVNC with the addition of autologous Schwann cells, breaking the barrier in the previous no-growth model. In the first stage, autologous Schwann cells were harvested from the contralateral peroneal nerve of the rabbit and expanded in culture. The Schwann cells were purified to >99 percent homogeneity using differential adhesion and antibody-compliment-mediated cytolysis. In the second stage, 6 cm of gluteal vein were harvested and used as a conduit that was filled with either Matrigel or a slurry of Matrigel and 10(6)/ml autologous Schwann cells (n=6 control and 6 experimental animals). The non-donor side peroneal was exposed and transected, leaving a gap of 6 cm. The filled gluteal vein graft (AVNC) was then anastomosed to the proximal and distal peroneal nerve stumps, and the rabbits were allowed to recover. Four months postoperatively, the animals were subjected to transcardiac perfusion with EM grade fixative. The grafts were analyzed at the light and electronmicroscopic levels, and showed excellent growth of nerve at 6 cm, the distal end of the AVNC.


A quantitative analysis of antigen-presenting cell function: activated B cells stimulate naive CD4 T cells but are inferior to dendritic cells in providing costimulation.
Ligation of CD28 on CD4 Th1 clones and freshly isolated mixtures of naive and memory CD4 T cells triggered their T cell receptors (TCR) is sufficient to induce the costimulatory signals necessary for interleukin 2 (IL-2) production by these cells. CTLA-4-reactive ligands expressed on antigen-presenting cells (APC) are critical in providing costimulatory signals to these T cell populations. We demonstrate that these activation characteristics apply equally to purified naive CD4 T cells. Because B cell blasts express CTLA-4-reactive ligands and high levels of adhesion and major histocompatibility complex class II molecules, they would be expected to engage both the TCR and CD28 and consequently stimulate IL-2 production by naive CD4 T cells. Using purified populations of cells in limiting dilution cultures, we have carried out a quantitative analysis of the interaction between naive CD4 T cells and either activated B or dendritic cells. We demonstrate that B cell blasts stimulate a high frequency of naive CD4 T cells. Slight differences in TCR signaling efficiency between the two APC types were observed. Even at optimal peptide concentrations, however, the amount of IL-2 made by individual T cells was fourfold lower in response to B cell blasts than to dendritic cells. This relative deficiency of activated B cells was due to their inability to optimally costimulate naive CD4 T cells.


Clustering-Triggered Efficient Room-Temperature Phosphorescence from Nonconventional Luminophores.
Pure organic room-temperature phosphorescence (RTP) and luminescence from nonconventional luminophores have gained increasing attention. However, it remains challenging to achieve efficient RTP from unorthodox luminophores, on account of the unsophisticated understanding of the emission mechanism. Herein, we propose a strategy to realize efficient RTP in nonconventional luminophores through incorporation of lone pairs together with clustering and effective electronic interactions. The former promotes spin-orbit coupling and boosts the consequent intersystem crossing, whereas the latter narrows energy gaps and stabilizes the triplets, thus synergistically affording remarkable RTP. Experimental and theoretical results of urea and its derivatives verify the design rationale. Remarkably, RTP from thiourea solids with unprecedentedly high efficiency of up to 24.5 % is obtained. Further control experiments testify the crucial role of through-space delocalization on the emission. These results will spur the future fabrication of nonconventional phosphors and advance the understanding of the underlying emission mechanism.


Cell cycle inhibitory activity of Piper longum against A549 cell line and its protective effect against metal-induced toxicity in rats.
Anticancer potential of Piper longum fruit against human cancer cell lines (DU-145 prostate, A549 lung, THP-1 leukemia, IGR-OVI-1 ovary and MCF-7 breast) as well as its in vitro and in vivo biochemical efficacy in A1Cl3-induced hepatotoxicity were evaluated in the rats. Dried samples were extracted with several solvents using soxhlet apparatus. Flavonoid content in chloroform, benzene, ethyl alcohol and aqueous extracts of fruit was 19, 14, 12 and 11 μg quercetin equivalent/mg of sample, respectively. Hexane extracts exhibited 90-92% cytotoxicity against most of the test cell lines (A549, THP-1, IGR-OVI-1 and MCF-7), while benzene extract displayed 84-87% cytotoxicity against MCF-7, IGR-OV-1 and THP-1 cell lines. Among extracts, hexane, benzene and acetone extracts demonstrated considerable cytotoxicity (91-95%) against A549 (lung cancer) cell line in Sulforhodamine B dye (SRB) assay. Cell cycle analysis revealed that hexane, benzene and acetone extracts produced 41, 63 and 43% sub-G1 DNA fraction, demonstrating cell cycle inhibitory potential of these extracts against A549 cell line. Chloroform, ethyl alcohol and aqueous extracts displayed 71, 64 and 65% membrane protective activity, respectively in lipid peroxidation inhibition assay. P. longum fruit extracts also ameliorated A1Cl3-induced hepatotoxicity, as indicated by alterations observed in serum enzymes ALP, SGOT and SGPT activity, as well as creatinine and bilirubin contents. In conclusion, study established the cytotoxic and hepatoprotective activity in P. longum extracts.


Hadaka Virus 1: a Capsidless Eleven-Segmented Positive-Sense Single-Stranded RNA Virus from a Phytopathogenic Fungus, Fusarium oxysporum.
The search for viruses infecting fungi, or mycoviruses, has extended our knowledge about the diversity of RNA viruses, as exemplified by the discovery of polymycoviruses, a phylogenetic group of multisegmented RNA viruses with unusual forms. The genomic RNAs of known polymycoviruses, which show a phylogenetic affinity for animal positive-sense single-stranded RNA [(+)RNA] viruses such as caliciviruses, are comprised of four conserved segments with an additional zero to four segments. The double-stranded form of polymycovirus genomic RNA is assumed to be associated with a virally encoded protein (proline-alanine-serine-rich protein [PASrp]) in either of two manners: a capsidless colloidal form or a filamentous encapsidated form. Detailed molecular characterizations of polymycoviruses, however, have been conducted for only a few strains. Here, a novel polymyco-related virus named Hadaka virus 1 (HadV1), from the phytopathogenic fungus Fusarium oxysporum, was characterized. The genomic RNA of HadV1 consisted of an 11-segmented positive-sense RNA with highly conserved terminal nucleotide sequences. HadV1 shared the three conserved segments with known polymycoviruses but lacked the PASrp-encoding segment. Unlike the known polymycoviruses and encapsidated viruses, HadV1 was not pelleted by conventional ultracentrifugation, possibly due to the lack of PASrp. This result implied that HadV1 exists only as a soluble form with naked RNA. Nevertheless, the 11 genomic segments of HadV1 have been stably maintained through host subculturing and conidiation. Taken together, the results of this study revealed a virus with a potential novel virus lifestyle, carrying many genomic segments without typical capsids or PASrp-associated forms.IMPORTANCE Fungi collectively host various RNA viruses. Examples include encapsidated double-stranded RNA (dsRNA) viruses with diverse numbers of genomic segments (from 1 to 12) and capsidless viruses with nonsegmented (+)RNA genomes. Recently, viruses with unusual intermediate features of an infectious entity between encapsidated dsRNA viruses and capsidless (+)RNA viruses were found. They are called polymycoviruses, which typically have four to eight dsRNA genomic segments associated with one of the virus-encoded proteins and are phylogenetically distantly related to animal (+)RNA caliciviruses. Here, we identified a novel virus phylogenetically related to polymycoviruses, from the phytopathogenic fungus Fusarium oxysporum The virus, termed Hadaka virus 1 (HadV1), has 11 (+)RNA genomic segments, the largest number in known (+)RNA viruses. Nevertheless, HadV1 lacked a typical structural protein of polymycoviruses and was not pelleted by standard ultracentrifugation, implying an unusual capsidless nature of HadV1. This study reveals a potential novel lifestyle of multisegmented RNA viruses.


Tinnitus: causes and clinical management.
Tinnitus is the perception of sound in the absence of a corresponding external acoustic stimulus. With prevalence ranging from 10% to 15%, tinnitus is a common disorder. Many people habituate to the phantom sound, but tinnitus severely impairs quality of life of about 1-2% of all people. Tinnitus has traditionally been regarded as an otological disorder, but advances in neuroimaging methods and development of animal models have increasingly shifted the perspective towards its neuronal correlates. Increased neuronal firing rate, enhanced neuronal synchrony, and changes in the tonotopic organisation are recorded in central auditory pathways in reaction to deprived auditory input and represent--together with changes in non-auditory brain areas--the neuronal correlate of tinnitus. Assessment of patients includes a detailed case history, measurement of hearing function, quantification of tinnitus severity, and identification of causal factors, associated symptoms, and comorbidities. Most widely used treatments for tinnitus involve counselling, and best evidence is available for cognitive behavioural therapy. New pathophysiological insights have prompted the development of innovative brain-based treatment approaches to directly target the neuronal correlates of tinnitus.


Osmotic versus conventional membrane bioreactors integrated with reverse osmosis for water reuse: Biological stability, membrane fouling, and contaminant removal.
This study systematically compares the performance of osmotic membrane bioreactor - reverse osmosis (OMBR-RO) and conventional membrane bioreactor - reverse osmosis (MBR-RO) for advanced wastewater treatment and water reuse. Both systems achieved effective removal of bulk organic matter and nutrients, and almost complete removal of all 31 trace organic contaminants investigated. They both could produce high quality water suitable for recycling applications. During OMBR-RO operation, salinity build-up in the bioreactor reduced the water flux and negatively impacted the system biological treatment by altering biomass characteristics and microbial community structure. In addition, the elevated salinity also increased soluble microbial products and extracellular polymeric substances in the mixed liquor, which induced fouling of the forward osmosis (FO) membrane. Nevertheless, microbial analysis indicated that salinity stress resulted in the development of halotolerant bacteria, consequently sustaining biodegradation in the OMBR system. By contrast, biological performance was relatively stable throughout conventional MBR-RO operation. Compared to conventional MBR-RO, the FO process effectively prevented foulants from permeating into the draw solution, thereby significantly reducing fouling of the downstream RO membrane in OMBR-RO operation. Accumulation of organic matter, including humic- and protein-like substances, as well as inorganic salts in the MBR effluent resulted in severe RO membrane fouling in conventional MBR-RO operation.


Socioeconomic inequalities in health in 22 European countries.
Comparisons among countries can help to identify opportunities for the reduction of inequalities in health. We compared the magnitude of inequalities in mortality and self-assessed health among 22 countries in all parts of Europe. We obtained data on mortality according to education level and occupational class from census-based mortality studies. Deaths were classified according to cause, including common causes, such as cardiovascular disease and cancer; causes related to smoking; causes related to alcohol use; and causes amenable to medical intervention, such as tuberculosis and hypertension. Data on self-assessed health, smoking, and obesity according to education and income were obtained from health or multipurpose surveys. For each country, the association between socioeconomic status and health outcomes was measured with the use of regression-based inequality indexes. In almost all countries, the rates of death and poorer self-assessments of health were substantially higher in groups of lower socioeconomic status, but the magnitude of the inequalities between groups of higher and lower socioeconomic status was much larger in some countries than in others. Inequalities in mortality were small in some southern European countries and very large in most countries in the eastern and Baltic regions. These variations among countries appeared to be attributable in part to causes of death related to smoking or alcohol use or amenable to medical intervention. The magnitude of inequalities in self-assessed health also varied substantially among countries, but in a different pattern. We observed variation across Europe in the magnitude of inequalities in health associated with socioeconomic status. These inequalities might be reduced by improving educational opportunities, income distribution, health-related behavior, or access to health care.


In vivo delivery of Gremlin siRNA plasmid reveals therapeutic potential against diabetic nephropathy by recovering bone morphogenetic protein-7.
Diabetic nephropathy is a complex and poorly understood disease process, and our current treatment options are limited. It remains critical, then, to identify novel therapeutic targets. Recently, a developmental protein and one of the bone morphogenetic protein antagonists, Gremlin, has emerged as a novel modulator of diabetic nephropathy. The high expression and strong co-localization with transforming growth factor-beta1 in diabetic kidneys suggests a role for Gremlin in the pathogenesis of diabetic nephropathy. We have constructed a gremlin siRNA plasmid and have examined the effect of Gremlin inhibition on the progression of diabetic nephropathy in a mouse model. CD-1 mice underwent uninephrectomy and STZ treatment prior to receiving weekly injections of the plasmid. Inhibition of Gremlin alleviated proteinuria and renal collagen IV accumulation 12 weeks after the STZ injection and inhibited renal cell proliferation and apoptosis. In vitro experiments, using mouse mesangial cells, revealed that the transfect ion of gremlin siRNA plasmid reversed high glucose induced abnormalities, such as increased cell proliferation and apoptosis and increased collagen IV production. The decreased matrix metalloprotease level was partially normalized by transfection with gremlin siRNA plasmid. Additionally, we observed recovery of bone morphogenetic protein-7 signaling activity, evidenced by increases in phosphorylated Smad 5 protein levels. We conclude that inhibition of Gremlin exerts beneficial effects on the diabetic kidney mainly through maintenance of BMP-7 activity and that Gremlin may serve as a novel therapeutic target in the management of diabetic nephropathy.


Comparing measurements of breast density.
Breast density measurements can be made from mammograms using either area-based methods, such as the six category classification (SCC), or volumetric based methods, such as the standard mammogram form (SMF). Previously, we have shown how both types of methods generate breast density estimates which are generally close. In this paper, we switch our attention to the question of why, for certain cases, they provide widely differing estimates. First, we show how the underlying physical models of the breast employed in the methods need to be consistent, and how area-based methods are susceptible to projection effects. We then analyse a set of patients whose mammograms show large differences between their SCC and SMF assessments. More precisely, 12% of 657 patients were found to fall into this category. Of these, 2.7% were attributable to errors either in the SMF segmentation algorithms, human error in SCC categorization or poor image exposure. More importantly, 9.3% of the cases appear to be due to fundamental differences between the area- and volume-based techniques. We conclude by suggesting how we might remove half of those discrepancies by introducing a new categorization of the SMF estimates based on the breast thickness. We note however, that this still leaves 6% of patients with large differences between SMF and SCC estimates. We discuss why it might not be appropriate to assume SMF (or any volume measure) has a similar breast cancer risk prediction capability to SCC.


Doxazosin modifies serotonin-mediated rabbit urinary bladder contraction. Potential clinical relevance.
5-Hydroxytryptamine (5-HT) induces rabbit detrusor contractions via 5-HT3 receptors. Similarly, 5-HT4 receptors are known to be present in the human bladder. Doxazosin, a non-selective alpha1 antagonist, is used for the symptomatic relief of bladder outflow obstruction. Previous work has shown that doxazosin inhibits 5-HT2-mediated platelet shape change. Hence, the aim of this study was to assess, using organ baths and autoradiography, whether doxazosin has any 5-HT-inhibiting activity in the rabbit detrusor. Detrusor strips from adult New Zealand White rabbits were placed in organ baths; phenoxybenzamine (10(-5) M) was added to block alpha-receptors. After KCl responses were assessed, the tissues were exposed to 10(-3) M 5-HT. Subsequently, the strips were incubated with doxazosin or ondansetron (10(-5) M; 5-HT3 antagonist) followed by a further exposure to 5-HT. In some experiments, after the initial 5-HT-induced contractions, the tissues were washed and then re-exposed to 5-HT. These latter experiments acted as controls. Low-resolution autoradiography was performed on detrusor sections to assess the effect of doxazosin on 5-HT binding. These sections were analyzed densitometrically. Doxazosin and ondansetron produced a significant reduction in 5-HT-mediated contractions. Inhibition by doxazosin was in a concentration-dependent manner. Autoradiography demonstrated a significant reduction in [3H]-5-HT binding by doxazosin. Doxazosin significantly inhibits 5-HT-mediated contractions in the rabbit detrusor. This effect appears to be mainly mediated via 5-HT3 receptor inhibition. Autoradiographic evidence suggests that doxazosin reduces 5-HT binding in the rabbit detrusor. The beneficial effects of doxazosin in bladder outflow obstruction may be due, at least in part, to 5-HT antagonism.


Leadership's role in support of online academic programs: implementing an administrative support matrix.
The proliferation of online education programs creates a myriad of challenges for those charged with implementation and delivery of these programs. Although creating and sustaining quality education is a shared responsibility of faculty, staff, and academic leaders, this article focuses on the pivotal role of leadership in securing the necessary resources, developing the organizational structures, and influencing organizational culture. The vital foundation for a successful outcome when implementing online education programs is the role of leadership in providing adequate and appropriate support. Abundant literature extols the roles of leadership in project management; however, there is a dearth of models or systematic methods for leaders to follow regarding how to implement and sustain online programs. Research conducted by the authors culminated in the development of an Administrative Support Matrix, thus addressing the current gap in the literature.